Process for producing substituted cyclopentadienes

ABSTRACT

A novel process for preparing a 5-substituted-1,3cyclopentadiene of the general formula, BY REACTING CYCLOPENTADIENYL THALLIUM WITH R-(CH2)n-O-CH2X wherein R is H, n is 1 to 3 and X is a halogen. The 5-substituted-1,3cyclopentadienes are useful intermediates for preparing therapeutically useful prostaglandins.

[54] PROCESS FOR PRODUCING SUBSTITUTED CYCLOPENTADIENES [72] Inventors:Ned M. Weinshenker, Sunnyvale, Calif.; Niels H. Andersen, Seattle,

Wash.

[73] Assignee: ALZA Corporation [22] Filed: Jan. 22, 1971 [21] Appl.No.: 108,967

[52] US. Cl ..260/6ll R, 260/611 A, 260/611 F,

260/468 R, 260/514 R 51 1m.c1 ..C07c 41/00 58 FieldofSearch ..260/6llR,611 A, 611 F Primary Examiner-Hemard Helfin AttorneyPaul Sabatine andSteven D. Goldby 1 Sept. 5, 1972 [5 7] ABSTRACT A novel process forpreparing a 5-substituted-l,3- cyclopentadiene of the general formula,

by reacting cyclopentadienyl thallium with R(CI-L OCH2X wherein R is H.

@( OUJ v n is 1 to 3 and X is a halogen. The 5-substituted-l,3-

cyclopentadienes are useful intermediates for preparmg therapeuticallyuseful prostaglandins.

3 Claims, No Drawings stituted-l,3-cyclopentadienes are useful as inter-1 I PROCESS FOR PRODUCING SUBSTITUTED CYCLOPENTADIENES BACKGROUND OF THEINVENTION The present invention relates to a novel and useful 5 processfor preparing 5-substituted-l,3-cyclopentadienes of the followingformula:

, oHZOwHmR wherein R is hydrogen,

and n is l to 3. The 5-substituted-l ,3-cyclopentadienes are prepared byreacting cyclopentadienyl thallium with a compound of the formula R(CH),,OCH X wherein R and n are as defined and X is a halogen, for example,chlorine, bromine or iodine. The S-submediates for preparing by artknown chemical methods therapeutically useful prostaglandins.

The prostaglandins are a naturally occurring group of long-chain,unsaturated, oxygenated fatty acids with useful therapeutic properties.The prostaglandins properties as recorded in Prostaglandins, ProgressInThe Chemistry of Fats And Other Lipids, Vol. IX, Part 2, pages 231 to273, 1968, Pergamon Press, broadly includes modifiers of smooth muscleactivity, gastric secretion, blood pressure, thereproductive system andthe like. The chemical art, because of the prostaglandins valuableproperties, has made available in J. Am. Chem. Soc., Vol. 91, pages 5675to 5677, 1969, a chemical synthesis for preparing the prostaglandins.

In the chemical synthesis, prior to this invention, seriousdisadvantages have been encountered by the prior art in one of thechemical steps leading to prostaglandins; mainly, in the addition ofcyclopentadienyl sodium or cyclopentadienyl lithium to halomethyl methylethers to produce S-methoxymethyll ,3- cyclopentadiene. One of thedisadvantages encountered by the prior art generally include theformation of an unwanted isomerization productl-methoxymethyll,3-cyclopentadiene. This product is formed because ofthe relatively high basicity of the cyclopentadienyl sodium or lithium,and also because of the continual presence and reacting of the lattercyclopentadienyls with the halo-methylmethyl ether and with newly formedS-substituted-l ,3-cyclopentadiene. The formation of isomerizationproducts further results in decreased yields ofS-substituted-l,3-cyclopentadiene and concomitantly therewith decreasedyields of valuable prostaglandins. I

Another disadvantage encountered with the use of cyclopentadienyl sodiumor lithium is the need for a tedious and difficult isolation steprequiring a buffer or an aqueous work-up of the reaction medium forremoving from the reaction medium unreacted cyclopentadienyl sodium orlithium and freshly formed sodium or lithium halides during theisolation of the essentially isomerically pureS-substituted-l,3-cyclopentadienes. The tedious chemical work-up isrequired not only to obtain the desired product, but also to prevent theformation of unwanted isomeric cyclopentadienes and low yields ofS-substituted-l,3-cyclopentadienes as mentioned supra. Thus, in view ofthe foregoing discussion, it can readily be seen that the art criticallyneeds a novel and improved chemical synthesis for preparing 5-substituted-l,3-cyclopentadienes that are useful for preparing valuableprostaglandins.

Accordingly, it is an object of the present invention to make availableto the art a novel chemical process for preparing 5-substitutedcyclopentadienes that essentially overcome the disadvantages encounteredby the prior art.

It is a further object of the present invention to provide a novelprocess for preparing 5-substituted-l,3- cyclopentadienes that can beused in art known chemical synthesis for producing useful therapeuticprostaglandins.

Still a further object of the invention is to provide a process forpreparing S-sI'IbStituted-l,3-cyclopentadienes wherein the process doesnot require extensive chemical work-up, and does not tend to produceunwanted isomerization products.

Yet still a further object of the invention is to provide a novelsynthesis for synthesizing 5-substituted-l ,3- cyclopentadienes whereinthe synthesis is reproducible, easy to carry out and is not subjected todecreased yield of the desired product.

These and other objects of the invention will be readily apparent to oneskilled in the art upon a study of the present disclosure and theaccompanying claims.

SUMMARY OF THE INVENTION This invention concerns both a novel and usefulimproved process for preparing 5-( lower alkoxy methyl) and5-(arylalkoxy methyl)-l,3-cyclopentadienes by reaction ofcyclopentadienyl thallium with a lower alkyl or with an arylalkylhalomethyl ether to produce essentially isomerically pure5-substituted-l ,3- cyclopentadienes. The .latter compounds are usefulfor preparing prostaglandins by known chemical processes. A

DETAILED DESCRIPTION OF INVENTIVE EMBODIMENTS In attaining the objectsand advantages of this invention, it has now been unexpectedly foundthat a novel and improved process for preparing 5-substituted-l ,3-cyclopentadienes can be made available to the art as represented by thefollowing general reaction:

wherein R is a member selected from the group consisting of hydrogen,phenyl, a-naphthyl and B-naphthyl, X is a halogen selected from thegroup consisting of chloro, bromo and iodo and n is l to 3, that is, analkylene such as methylene, ethylene, propylene and isopropylene.

The novel reaction of the invention is usually carried out by intimatelycontacting and reacting the reactants at a temperature of about C to25C, usually at l0C to 5C, in an inert atmosphere and in the presence ofan inert organic solvent. The reaction is usually carried out byreacting stoichiometric amounts or an excess of the reactants undernormal atmospheric pressure or at elevated pressures up to 5atmospheres. Generally, a suitable solvent is any solvent that does notadversely affect the reaction such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, methyl ethyl ether, dioxane,benzene, and the like. Representative of inert atmospheres include theinert gases such as argon, and the like, and other inert gases such asnitrogen, and the like, and mixtures thereof. Exemplary of startingethers suitable for the above reaction are the commercially availableand art known ethers such as 2- bromoethyl'methyl ether; bromomethylmethyl ether; bromomethyl propyl ether; bromomethyl isopropyl ether;chloromethyl methyl ether; iodomethyl ethyl ether; bromomethyl benzylether; and the like as disclosed in]. Org. Chem., Vol. 26, pages 3,761to 3,769, 1961; Chem. Abst.,.Vol. 52, page 16,201; ibid., Vol. 53, page1,105; ibid., Vol. 56, page 7,223; ibid., Vol. 58, page 1,331; andibid., Vol. 65, page 2,239. The cyclopentadienyl thallium used accordingto the spirit of the invention is also commer-cially available and it isfurther known to the art in (hem. Abst., Vol. 52, page 16,366; and inBelgian Pat. No. 620,663.

The following examples are representative of embodiments of the presentinvention and these examples are not to be construed as limiting asthese and other embodiments will be readily apparent to those versed inthe art in the light of the present disclosure and the accompanyingclaims.

EXAMPLE 1 Preparation of 5-(methoxymethyl)-l,3-cyclopentadiene. A drythree-necked flask equipped with a thermometer, a stirrer and aninlet-outlet port is charged with 500 g (1.86 moles) of cyclopentadienylthallium and 1,500 ml of anhydrous diethyl ether in an inert argonatmosphere. The reaction mixture is next cooled to about 10C to 15C and220 g (1.76 moles) of anhydrous bromomethyl methyl ether is addeddropwise and with constant stirring to the reaction medium. Theinternalreaction temperature is maintained at about -lC during theaddition of the halogenated ether. After all the halogenated ether isadded, the reaction mixture is filtered to remove unreactedcyclopentadienyl thallium and thallium bromide to give an ether solutioncontaining the desired -(methoxymethyl)-l,3- Cyclopentadiene. The inertsolvent can be evaporated at about 20C or the solution containing the 5-(methoxymethyl)-l,3-cyclopentadiene can be used as is in the abovementioned organic synthesis for preparing prostaglandins.

EXAMPLE 2 be accomplished by evaporating the ether at about 20C.

EXAMPLE 3 cyclopentadiene; 5-( a-naphthylmethoxymethyl)-l ,3-cyclopentadiene.

The S-methoxymethyll ,3-cyclopentadie nes produced by this inventionhave known utility for the production of stereo-controlled synthesis ofpharmaceutically active prostaglandins as set forth, for example, in J.Am. Chem. Soc., Vol. 91, pages 5,675 to 5,678, 1969. The compound isused in the Diels-Alder reaction and in the reaction listed in thereferences as 1 through 16 inclusive to yield prostaglandins PGE (1 1a,15(S)-dihydroxy-9-oxo-5-cis, 13-trans-prostadienoic acid) andPGF201(90,1 1a,15(S)-trihydroxy- 5-cis,l3-trans-prostadienoic acid).Both of these prostaglandins are useful as therapeutics, such as, forinducing labor, the stimulation of smooth muscles, the terminating ofpregnancy, and the like.

As is evident from the above examples and discussion, it is readilyapparent that this invention makes available to the art an unobviousmethod for producing 5-substituted-1,3-cyclopentadienes that can besuccessfully used for synthesizing valuable prostaglandins without beingsubjected to the disadvantages associated with the prior art. And, whilevarious illustrative embodiments of the invention have been describedwith particularity, it will be understood that various modificationswill be apparent and can be readily made by those skilled in the artwithout departing from the scope and the spirit of the invention.

We claim:

1. A process for preparing cyclopentadienes of the general formulawherein R is a member selected from the group consisting essentially ofhydrogen,

and n is 1 to 3 inclusive wherein said process comprises reacting atabout C to 25C in an inert atmosphere and in the presence of an inertorganic solvent, a compound of the formula with a compound of theformula XCH O(CH ),,R wherein X is a halogen, R and nare as defined toproduce the desired cyclopentadienes.

2. A process for producing a compound according to claim 1 wherein thecompound is 5-(methoxymethyl)- 1 ,3-cyclopentadiene.

3. A process for producing a compound according to claim 1 wherein thecompound is S-(benzyloxymethyD- 5 1 ,3,-cyclopentadiene.

2. A process for producing a compound according to claim 1 wherein thecompound is 5-(methoxymethyl)-1,3-cyclopentadiene.
 3. A process forproducing a compound according to claim 1 wherein the compound is5-(benzyloxymethyl)-1,3-cyclopentadiene.